The underlying pathophysiology of schizophrenia (SCZ) appears to involve the dopamine (DA) system. Using Positron Emission Tomography (PET) with DA antagonists, the PI's long term goal is to quantify these abnormalities upon diagnosis and during treatment. The PI's two main hypotheses are that extracellular dopamine (DAe) and/or D4 receptor elevations exist in SCZ and are measurable by PET. These abnormalities may effect the D2 Bmax quantification depending on the ligand employed. If hypothesis 1 is true, then patients with SCZ will release a greater surge of DA in response to drugs than normals. To test this hypothesis, the first aim is to quantify DA release in vivo. The second aim is to determine how Bmax measures of the two radioligands, N-methylspiperone (NMSP) and raclopride (RAC), are affected by DAe changes. If the binding differs, such as may occur in psychosis, this could effect the PET quantification in SCZ.If hypothesis 2 is true, the PI expects to see D4 differences between SCZ and normals. The third aim is designed to image the D2-like DA receptor subtype D4 to determine its contribution to PET measures in SCZ. Both hypotheses could coexist according to Grace's theory; frequent DA "phase" firing could result in an increased DA surge and low baseline tonic DA. This could explain abnormal DAe response and elevated D4 receptor densities in SCZ, respectively. In Aims 1 and 2, the PI will use rodent models and baboon imaging with microdialysis and kinetic measures to develop valid measures of DAe. Microdialysis and subcellular fractionation studies will allow a direct measurement of the possible mechanisms of receptor internalization. The use of baboon provides the opportunity for multiple doses and procedures, which enhance the understanding of human mechanisms. Drug perturbations will alter DAe in baboon and human PET studies which will be mathematically modeled based on the basic animal work. The effect of DAe on Bmax PET measures with NMSP and RAC, will then be determined in humans. In Aim 3, D4 receptor Bmax measures will be estimated in vivo using 11C RAC. A mathematical approach will be used to quantify DAe and Bmax simultaneously. Simulation studies will employ a realistic use of physical imaging factors, and clarify the appropriate algorithm to employ in the analysis. A future benefit from these studies will be the potential to measure not only D2-like DA receptors (D2, D3, D4), but also DAe levels and their effects on imaging psychotic illness.